In order for a substance to be defined as a Selective Estrogen Receptor Modulator (SERM), the following criteria proving this mode of action need to be shown:

• Estrogen receptor agonistic or antagonist activity in various tissues- in this case the effect on menopausal symptoms, the bone, breast tissue, and on the uterus;
• Blocking of the activity by an estrogen receptor blocker (such as raloxifene) - in order to determine whether the effect is through estrogen receptors.
• Blocking the bondage of estrogen to the estrogen receptors- when Femarelle^® and E₂ are administered simultaneously_, Femarelle^® blocks the bondage of E₂ in all tissues, proving Femarelle^®'s antagonistic properties.

In clinical studies, Femarelle^® relieved menopausal symptoms and increased bone mineral density (agonistic activity) while not affecting sex steroid hormone levels or endometrial thickness (antagonistic activity). Studies in vivo showed that Femarelle^® stimulates the activity of creatine kinase (CK), a marker of estrogen receptor activation, in skeletal tissues of female rats (agonistic activity). In the uterus, however, CK was activated only by E₂ and not by Femarelle^® (antagonistic activity). Furthermore, Femarelle^® was shown to activate osteoblast activity, promoting bone build-up through estrogen receptor activation (agonistic activity).

In the present study, CK specific activity was monitored in various tissues following the simultaneous administration of Femarelle^® and E₂:

· In vivo: Epiphyseal cartilage, diaphyseal bone, thymus, pituitary gland and in the uterus were monitored in intact and ovariectomized female rats.

· In vitro: Human cultured osteoblasts and human umbilical artery smooth muscle cells were monitored.

Results

The results showed that the estrogen receptors bound preferentially with Femarelle^® in the bone tissue, thymus and the pituitary gland. In the uterus Femarelle^® blocked the effect of E₂, demonstrating its antagonistic effect on estrogen receptors in this organ.

Conclusion

Femarelle^® bonds to all estrogen receptors; it displays either agonistic or antagonistic activity, depending on the tissue. In the uterus, Femarelle's antagonistic activity was demonstrated following its blockage of the estrogen receptors to the effect of E₂. This study provides additional proof that Femarelle^® works as a Selective Estrogen Receptor Modulator (SERM).

Publication

Journal of Steroid Biochemistry and Molecular Biology 2007;104:252-258: "DT56a (Femarelle): a natural selective estrogen receptor modulator (SERM)"; Somjen D and Yoles I.